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Metallaphotoredox-catalysed sp3–sp3 cross-coupling of carboxylic acids with alkyl halides

Nature volume 536, pages 322–325 (2016)Cite this article

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Abstract

In the past 50 years, cross-coupling reactions mediated by transition metals have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across many areas of chemical research1. However, the construction of a bond between two sp3-hybridized carbon atoms, a fundamental unit of organic chemistry, remains an important yet elusive objective for engineering cross-coupling reactions2. In comparison to related procedures with sp2-hybridized species, the development of methods for sp3–sp3 bond formation via transition metal catalysis has been hampered historically by deleterious side-reactions, such as β-hydride elimination with palladium catalysis or the reluctance of alkyl halides to undergo oxidative addition3,4. To address this issue, nickel-catalysed cross-coupling processes can be used to form sp3–sp3 bonds that utilize organometallic nucleophiles and alkyl electrophiles5,6,7. In particular, the coupling of alkyl halides with pre-generated organozinc8,9, Grignard10 and organoborane11 species has been used to furnish diverse molecular structures. However, the manipulations required to produce these activated structures is inefficient, leading to poor step- and atom-economies. Moreover, the operational difficulties associated with making and using these reactive coupling partners, and preserving them through a synthetic sequence, has hindered their widespread adoption. A generically useful sp3–sp3 coupling technology that uses bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be valuable. Here we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp3–sp3 bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. This metallaphotoredox protocol is suitable for many primary and secondary carboxylic acids. The merit of this coupling strategy is illustrated by the synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.

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Figure 1: Carboxylic acids as coupling partners in a metallaphotoredox-mediated process to form sp3–sp3 bonds.
Figure 2: Proposed mechanism for the metallaphotoredox-mediated cross-coupling of carboxylic acids to generate sp3–sp3 bonds.
Figure 3: Carboxylic acid and alkyl halide scope in the dual nickel-photoredox catalysed sp3–sp3 coupling reaction.
Figure 4: Application of two metallaphotoredox strategies to the synthesis of tirofiban.

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Acknowledgements

Financial support was provided by NIHGMS (R01 GM093213-01); we acknowledge gifts from Merck, AbbVie, and Bristol-Myers Squibb. C.P.J. thanks Marie Curie Actions for an international outgoing fellowship (PIOF-GA-2013-627695). S.A. thanks the Deutsche Forschungsgemeinschaft (DFG) for a postdoctoral fellowship (AL 1860/2-1).

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  1. Craig P. Johnston and Russell T. Smith: These authors contributed equally to this work.

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  1. Merck Center for Catalysis at Princeton University, Princeton, 08544, New Jersey, USA

    Craig P. Johnston, Russell T. Smith, Simon Allmendinger & David W. C. MacMillan

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Contributions

C.P.J., R.T.S. and S.A. performed and analysed experiments. C.P.J., R.T.S., S.A. and D.W.C.M. designed experiments to develop this reaction and probe its utility, and wrote the paper.

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Correspondence to David W. C. MacMillan.

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The authors declare no competing financial interests.

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Nature thanks E. Peterson and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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This file contains Supplementary Text and Data, Supplementary Figures 1-4, additional references and NMR Spectra. (PDF 8665 kb)

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Johnston, C., Smith, R., Allmendinger, S. et al. Metallaphotoredox-catalysed sp3–sp3 cross-coupling of carboxylic acids with alkyl halides. Nature 536, 322–325 (2016). https://doi.org/10.1038/nature19056

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